The hypothesis to be tested is that the hyperinsulinemia and insulin antagonism of obesity is due to increased dietary carbohydrate intake causing enhanced pancreatic insulin secretion which, in turn, leads to an impairment of insulin activity on target tissues. The first part of the postulate will be evaluated by feeding normal weight subjects iso- and hypercaloric diets of varying carbohydrate and fat content for 5 day periods. An enhancement of insulin secretion after this period of time would have to be secondary to dietary factors since negligible amounts of weight gain would have occurred. The second part of this postulate will be tested in an in vitro cultured muscle cell system which responds to insulin. If such cells grown in the presence of insulin manifest an impaired response to the hormone, a valuable model in which to study insulin antagonism will have been established. The cultured muscle cell system will also be used to study several other insulin antagonists; growth hormone (GH) glucocorticoid and free fatty acids. In addition, the possibility that an intracellular glucose fatty acid cycle is responsible for the effect of GH on carbohydrate metabolism of muscle will be tested by measuring oxidation of triglycerides in the diaphragms of saline and GH-injected hypophysectomized rats. Finally, the insulin antagonism of chronic renal failure will studied in rats rendered uremic by 5/6 nephrectomy.